One of the strongest clinical associations with autoantibodies directed to components of the Ro/La ribonucleoprotein complex is the development of congenital heart block (CHB) in an offspring, an alarming prospect facing 2% of primigravid mothers with these reactivities. The risk of CHB is 10-fold higher in subsequent pregnancies of women who have previously had an affected child. No preventive therapies have been successful and complete block has never been reversed. Experimental evidence supports a role of Toll-like receptor signaling in the pathogenesis of CHB. Since hydroxychloroquine (HCQ) inhibits this implicated pathway, two studies were initiated: 1) a case control study that demonstrated a reduction in risk of disease in HCQ-exposed fetuses of anti-Ro antibody-positive women with SLE, and 2) a historical cohort study in which the recurrence rate of CHB was decreased by 70%. Based on these encouraging bench-to-bedside results, an open label prospective study using Simon's 2-Stage approach was initiated via a pilot R03 with the hypothesis that HCQ significantly reduces the recurrence rate of CHB. Exploiting Simon's 2-Stage design, the goal was to complete enrollment of 19 mothers in Stage I whose previous pregnancies were complicated by CHB with the intent of an R01 application should fewer than 3 recurrent cases occur. As of February 2014 with 32 pregnancies enrolled, 23 completed (19 on no potentially confounding medications) and 2 beyond the 26th week (vulnerability rare >26 weeks), only one case of complete block occurred. These data support commencement of Stage II. Accordingly, Specific Aim 1 is to complete Stage II of the open label Phase II trial, entitled Preventive Approach To Congenital Heart Block with Hydroxychloroquine (PATCH), in pregnant women who have had a previous CHB child. The protocol remains identical, with HCQ initiated by 10 weeks gestation. Serial echocardiograms and evaluation of maternal and cord blood biomarkers (HCQ levels, IFN? signatures, autoantibody titers) address maternal compliance, pathobiology and efficacy. Over 5 years, up to 35 subjects will be enrolled (to assure no potentially confounding medications). Study governance remains at NYU. An IND has been maintained. Ultimately, HCQ will be considered efficacious if <6 cases occur among a total of 54 subjects. A positive result will likely change the management of all anti-Ro positive women who have had a previous child with CHB and illustrate the importance of translational science. A potential prevention would justify screening all pregnant women with anti-Ro antibodies, particularly relevant since the majority of mothers of affected children are themselves totally asymptomatic. Specific Aim 2 addresses the ophthalmologic safety of HCQ exposure during pregnancy. Despite the rarity of safety issues reported in over 300 children whose mothers were treated with varied doses of HCQ for rheumatic disease during pregnancy, concerns remain since HCQ interferes with lysosomal metabolism and thus may be damaging to retinal neurons. Data on retinal development in children age 5 and controls (matched for race and gestational age at birth) obtained by optical coherence tomography are expected to provide further reassurances regarding the safety of HCQ exposure during pregnancy.